Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis

We have previously shown that tumor necrosis factor (TNF)α produced from primary tumor-induced expression of two endogenous Toll-like receptor 4 (TLR4) ligands, S100A8 and serum amyloid A3 (SAA3), in pre-metastatic lungs. However, mechanistic details of the signaling network and relevance to pulmonary physiology are poorly understood. Here, we identify Clara cells as a control tower of the network. Clara cell ablation by naphthalene suppressed pulmonary recruitment of CD11b+TLR4+ cells and spontaneous lung metastasis. Clara cells turned out to express TLR4 through which SAA3 was auto-amplified. Reciprocal bone marrow transplantation between wild-type and TLR4 knockout mice demonstrated that pulmonary TLR4+ Clara cells could be derived from bone marrow. SAA3-induced TNFα expression in both alveolar type II cells and macrophages. Primary co-cultures of alveolar type II cells and Clara cells revealed that the induction of TNFα in alveolar type II cells was dependent on the Clara cell-mediated amplification of SAA3. SAA3 induction by bacterial endotoxin also required both Clara cells and TLR4. Thus, pulmonary metastatic soil may feature deregulation of homeostatic inflammatory responses to constant assaults of microbes with endotoxin.